Despite the promise of targeted therapies, cytotoxic chemotherapy remains the mainstay of treatment for triple negative breast cancer (TNBC) patients. Due to the heterogeneity of TNBC, the identification of biomarkers is critical to select patients for various therapies. We recently identified TNBC subtypes with corresponding molecular drivers and preclinical models to develop effective therapeutic approaches. Herein, we propose three specific aims to test the following interrelated hypotheses: In TNBC patients with the luminal, androgen receptor (AR)-expressing subtype, AR and PISK signaling synergistically drive tumor growth, and treatment of these patients with an AR antagonist (bicalutamide) in combination with a PISK pathway inhibitor will be an effective therapy. In the remaining 90% of TNBC patients, the high frequency of p5S mutations and PISK signaling pathway alterations in their tumors will result in therapeutic vulnerability to the genotoxic agent cisplatin given in combination with a PISK inhibitor. Specific Aim 1: a) To evaluate the efficacy, as measured by clinical benefit rate of bicalutamide + the pan-PISK inhibitor (GDC-0941) in patients with AR+ metastatic TNBC. b) To evaluate the efficacy, as measured by overall response rate of cisplatin + GDC-0941 versus cisplatin alone in patients with AR- metastatic TNBC. We will determine if a set of genomic markers can predict sensitivity or resistance to these therapeutic regimens tested. Specific Aim 2: To determine mechanisms of inherent and acquired resistance to cisplatin and PISK inhibitors in the TNBC setting. Specific Aim S: To develop validated clinical biomarkers for TNBC subtyping and use in selection of patients for future clinical trials or new standard treatments. Comprehensive analysis of well-characterized tumors from patients on hypothesis-driven clinical trials will allow discovery of mechanisms of sensitivity and resistance as well as biomarkers that can be used in the development of new treatment regimens and selection of patients for future trials. RELEVANCE (See instructions); The proposed research will investigate new therapeutic approaches for triple negative breast cancer (TNBC) based on the molecular drivers of the disease. We are translating our preclinical findings to innovative, targeted, subtype-specific clinical trials for TNBC patients. We will discover new biomarkers to predict response and resistance to known (cisplatin and bicalutamide) and new therapies (PISK inhibitors); the latter has implications for use in many cancer types.